Control of Yeast Life Span

卡路里限制(CR)，即减少每日卡路里摄入量，可以延长小鼠和酵母的寿命。长期以来，CR一直被认为通过减少细胞能量代谢产生的活性氧物种(ROS)来延长寿命。目前尚不清楚CR是否只减少了ROS的产生，或者还诱导了一种保护细胞免受ROS潜在损害的状态。我们对控制酵母沉默的研究为了解CR的分子机制提供了新的见解。沉默，基因表达的可逆抑制，在老酵母中的变化，并在酵母对CR的反应中发挥作用。我们分离出了模拟老化酵母沉默表型的突变。值得注意的是，我们发现了已知可以延长酵母寿命的突变，并确定了与小鼠途径同源的途径，这些途径的表达在CR和衰老过程中发生变化。我们的突变体中有60%的线粒体有缺陷，这是哺乳动物细胞老化的标志。因此，我们对控制沉默的遗传途径的识别也发现了受CR和小鼠衰老调节的途径。我们还分离出了第二组突变，这些突变可以阻止陈年酵母的沉默表型。这些突变体识别染色质重塑因子和染色质成分。染色质的变化可能是调节转录以响应CR的途径的终点。因此，我们的两组突变体很可能识别控制寿命的信号产生和信号响应末端。这项建议的目的是了解基因沉默和寿命是如何控制的，以应对有缺陷的线粒体和CR。我们假设CR和我们的突变体诱导了细胞通常用来对能源变化做出反应的途径，并通过特定的染色质成分控制衰老速度。为了验证这些假说，我们将追求以下具体目标：目标1.我们的突变体确定了哪些调节寿命和沉默的途径？目的2.我们对沉默突变的控制是否像CR一样延缓了衰老表型的出现？目的3.哪些延长寿命的基因受CR控制，并在目标1和2中识别和描述了哪些途径？这项工作的结果将阐明CR介导的寿命延长的分子机制，并为哺乳动物系统提供一个模型。

Caloric restriction (CR), i.e. the reduction of the daily caloric intake, can prolong the life span of mice and yeast. CR has long been thought to extend life span by reducing the number of reactive oxygen species (ROS) produced by cellular energy metabolism. It is not known if CR only reduces the production of ROS or also induces a state that protects the cell from potential damage from ROS. Our studies on the control of yeast silencing provide novel insights into the molecular mechanisms of CR. Silencing, the reversible repression of gene expression, changes in old yeast and plays a role in the yeast response to CR. We isolated mutations that mimic the silencing phenotype of aged yeast. Remarkably, we found mutations known to increase yeast life span and identified pathways homologous to mouse pathways whose expression changes during CR and aging. 60 percent of our mutants have defective mitochondria, a hallmark of aging in mammalian cells. Thus, our identification of genetic pathways that control silencing has also identified pathways modulated by CR and aging in mice. We have also isolated a second set of mutations that block the silencing phenotype of aged yeast. These mutants identify a chromatin remodeling factor and chromatin components. Changes in chromatin are the likely endpoints of pathways that modulate transcription in response to CR. Thus, our two sets of mutants most likely identify signal generating and signal responding ends of pathways that control life span. The goal of this proposal is to understand how gene silencing and life span are controlled in response to defective mitochondria and CR. We hypothesize that CR and our mutants induce pathways that the cell normally uses to respond to changes in energy source, and to control the rate of aging through specific chromatin components. To test these hypotheses, we will pursue the following specific aims: Aim 1. What life span- and silencing-modulating pathways do our mutants identify? Aim 2. Do our control of silencing mutations delay the appearance of aging phenotypes in the same way as CR? Aim 3. Which life span extending genes are controlled by CR and the pathways identified and characterized in aims 1 and 2? The results of this work will elucidate the molecular mechanisms of CR-mediated life span extension and provide a model for mammalian systems.